Protection and cell repair strategies for neurodegenerative diseases such as Parkinson’s Disease (“PD”) depend on well-characterized candidate human stem cells that are robust and show promise for generating the neurons of interest following stimulation of inherent brain stem cells or after cell transplantation. These stem cells must also be expandable in the culture dish without unwanted growth and differentiation into cancer cells, they must survive the transplantation process or, if endogenous brain stem cells are stimulated, they should insinuate themselves in established brain networks and hopefully ameliorate the disease course.
The studies proposed for the CIRM Research Leadership Award have three major components that will help better understand the importance and uses of stem cells for the treatment of PD, and at the same time get a better insight into their role in disease repair and causation. First, we will characterize adult human neural stem cells from control and PD brain specimens to distinguish their genetic signatures and physiological properties of these cells. This will allow us to determine if there are stem cells that are pathological and fail in their supportive role in repairing the nervous system. Next, we will investigate a completely novel disease initiation and propagation mechanism, based on the concept that secreted vesicles from cells (also known as “exosomes”) containing a PD-associated protein, alpha-synuclein, propagate from cell-to cell. Our hypothesis is that these exosomes carry toxic forms of alpha-synuclein from cell to cell in the brain, thereby accounting disease spread. They may do the same with cells transplanted in patients with PD, thereby causing these newly transplanted cells designed to cure the disease, to be affected by the same process that causes the disease itself. This is a bottleneck that needs to be overcome for neurotransplantation to take its place as a standard treatment for PD.
Our studies will address disease-associated toxicity of exosomal transmission of aggregated proteins in human neural precursor stem cells. Importantly, exosomes in spinal fluid or other peripheral tissues such as blood might represent a potentially early and reliable disease biomarker as well as a new target for molecular therapies aimed at blocking transcellular transmission of PD-associated molecules.
Finally, we have chosen pre-clinical models with α-synucleinopathies to test human neural precursor stem cells as cell replacement donors for PD as well as interrogate, for the first time, their potential susceptibility to PD and contribution to disease transmission. These studies will provide a new standard of analysis of human neural precursor cells at risk for and contributing to pathology (so-called “stem cell pathologies”) in PD and other neurodegenerative diseases via transmission of altered or toxic proteins from one cell to another.

Statement of Benefit to California:

According to the National Institute of Health, Parkinson’s disease (PD) is the second most common neurodegenerative disease in California and the United States (one in 100 people over 60 is affected) second only to Alzheimer’s Disease. Millions of Americans are challenged by PD, and according to the Parkinson’s Action Network, every 9 minutes a new case of PD is diagnosed. The cause of the majority of idiopathic PD is unknown. Identified genetic factors are responsible for less than 5% of cases and environmental factors such as pesticides and industrial toxins have been repeatedly linked to the disease. However, the vast majority of PD is thought to be etiologically multi-factorial, resulting from both genetic and environmental risk factors. Important events leading to PD probably occur in early or mid adult life. According to the Michael J. Fox Foundation, “…there is no objective test, or reliable biomarker for PD, so rate of misdiagnosis is high, and there is a seriously pressing need to develop better early detection approaches to be able to attempt disease-halting protocols at a non-symptomatic, so-called prodromal stage.”
The proposed innovative and transformative research program will have a major direct impact for patients who live in California and suffer from PD and other related neurodegenerative diseases. If these high-risk high-pay-off studies are deemed successful, this new program will have tackled major culprits in the PD field. They could lead to a better understanding of the role of stem cells in health and disease. Furthermore they could greatly advance our knowledge of how the disease spreads throughout the brain which in turn could lead to entire new strategies to halt disease progression. In a similar manner these studies could lead to ways to prevent the disease from spreading to cells that have been transplanted to the brain of Parkinson’s patients in an attempt to cure their disease. This is critical for neurotransplantation to thrive as a therapeutic approach to treating PD. In addition, if we extend the cell-to-cell transmissible disease hypothesis to other neurodegenerative diseases, and cancer, the studies proposed here represent a new diagnostic approach and therapeutic targets for many diseases affecting Californians and humankind in general.
This CIRM Research Leadership Award will not only have an enormous impact on understanding the cause of PD and developing new therapeutic strategies using stem cells and its technologies, this award will also be the foundation of creating a new Center for Translational Stem Cell Research within California. This could lead to further growth at the academic level and for the biotechnology industry, particularly in the area regenerative medicine.

Review Summary:

The candidate principle investigator (PI) is an established scientist leading an active program in neural stem cell (NSC) research. The PI’s research has encompassed neural development, astroglial biology and neural regeneration with particular attention to the biology of neural progenitor cells. The proposed research will focus on elucidating the molecular pathology underlying Parkinson’s disease (PD). Studies will center on exploring the hypothesis that an infectious, toxic, prion-like protein transmitted from cell to cell via secreted vesicles, called exosomes, accounts for the spread and progression of PD within the brain. The proposed experiments will investigate differences and deficiencies of stem cell pathologies in NSCs derived from PD patients, analyze the role of exosomes in causing PD pathologies in midbrain neuronal cultures, and study the transmission of exosomes with in vivo, preclinical transplantation models. These studies should advance an understanding of PD and may point toward new therapeutic strategies.
Reviewers appreciated the focus of the PI’s proposal on an important problem, the pathology of PD, and cited the innovative and interesting hypothesis that will be addressed by the research aims. The proposed study was viewed as comprehensive. However, reviewers found many deficiencies, assumptions and poorly supported extrapolations in the research plan. Although the exosome hypothesis for PD was described by other researchers several years ago, little compelling evidence in support of this theory has been published by the PI or other research groups. Additionally, reviewers questioned the PI’s basic assumption that pathological properties of NSCs in PD patients interferes with endogenous repair mechanisms and underlies disease development.
The candidate was recognized as an accomplished leader in the field of NSC research. Reviewers praised his/her scientific integrity, productivity and important contributions to neuroscience research. However, reviewers expressed concern that the PI has published little in the PD field and that the proposed research represents a significant departure from the candidate’s area of expertise. Reviewers cited the PI’s solid and well regarded impact on the study of NSCs and noted his/her funding by the NIH and presentations at a number of scientific meetings. The applicant’s has demonstrated leadership in service as an associate editor of a major journal, as chairman of an NIH study section and as director of a university neurosciences institute. Enthusiastic letters from distinguished neuroscientists and stem cell biologists praised the candidate’s thoughtful, creative and important research and solid contributions. They further stressed his/her notable leadership experience and abilities.
Reviewers expressed mixed assessments concerning the applicant institution’s commitment and the research environment. The institution’s recruitment package was viewed as solid but not outstanding. The institute is actively engaged in translational and clinical PD studies, but has only a very limited program in basic research. Reviewers felt that the candidate would bring leadership in fundamental studies of disease mechanisms and basic NSC research but questioned whether the institution could provide a critical mass of personnel, essential resources, core facilities, and an appropriate environment to enable achievement of the project goals.
In summary, this is an application from an established leader in NSC biology to pursue research focused on disease mechanisms in PD. Strengths of the proposal include the quality of the PI, the focus of the project on an interesting hypothesis, and the leadership in basic science that the candidate would bring to the applicant institution. Weaknesses included deficiencies in the research plan, the limited track-record of the PI in PD research and an institutional environment lacking adequate support for basic science investigations.

Programmatic review:

During programmatic discussion some GWG members cited a need to broaden stem cell leadership not only at the large universities but also at the smaller institutions as well. They felt that the candidate’s recruitment would strengthen the applicant institution and provide leadership and strength in basic research. The need for increased research focused on Parkinson’s Disease was also cited by some reviewers.

A motion to recommend the application for funding carried with a majority vote. Because more than 35% of GWG members opposed the motion, opponents have exercised their right to have that position reported to the ICOC. The consensus statement from this group is as follows:

“Despite the facts that the applicant has many excellent attributes, that Parkinson's disease is a key area of interest, and that the applicant institution may deserve additional consideration, our opinion is that the application clearly falls short in several critical scientific areas that outweigh the programmatic concerns and do not justify a recommendation for funding. We believe that the people of California depend upon us to make recommendations based on our scientific expertise, for outcomes that are most likely to impact medicine and the health and treatment of their citizens. We believe that their money can be better spent”.